Safety, Tolerability, Pharmacokinetics, and Antitumor Study of ADCT-601 to Treat Advanced Solid Tumors. ADC Therapeutics.
An AXL armed antibody. This is in addition to their CD19, CD25, CD22, PSMA and DLK1 ADCs. This company is probably worth a few billion.

A Study of Lobaplatin/Etoposide With or Without Anlotinib Maintenance Therapy in Patients with ES-SCLC.
Well, China is here. Between anlotinib and apatanib, you have two home-grown TKIs from China. Lobaplatin is a Chinese platinum as well. China is sort of like the new Japan for pharma.

Clinical Trial Using the Proteolytic Fraction P1G10 From V. Cundinamarcensis to Heal Diabetic Foot Ulcer. Federal University of Minas Gerais.
Not for me but possibly a good opportunity for would-be in-licensors out there.

Comparison of the Efficacy & Safety of Resusix with FP24 in Patients with Acquired Coagulopathy. Entegrion, Inc.
Pretty interesting alternative to FFP.

Biopharma/Investing
————————-
Celgene is going to have a rough next decade. With 12 of 15 billion in revenue disappearing in the form of generic Revlimid, Otezla and Abraxane, I’m not sure CART, JAK and S1P1 will do the trick. The company spent a lot of money on buybacks and finds itself in a potent net debt position. Novartis reported $20m in revenue in the second full quarter of their CART product Kymriah. You know what to do!

Papers I’ve Read
———————
Mutant APP and Amyloid Beta-induced defective autophagy, mitophagy, mitochondrial structural and functional changes and synaptic damage in hippocampal neurons from Alzheimer’s Disease. Reddy et al. Hum Mol Genet 2018.
Papers like this should not be published. The authors find impaired mitochondria in AD neurons. No shit. Things go wrong, horribly wrong in Alzheimer’s brains. Biological processes are upended and synaptic integrity collapses. Why? Well, we know that mAPP (mutated amyloid precursor protein) patients suffer early-onset AD, which certainly implicates A-beta. Despite this, all attempts to neutralize A-beta have not changed outcomes in AD. This is probably due to a temporal-treatment mismatch. But this paper tries to suggest impaired mitophagy and mitochondrial function as a direct consequence of AB. It certainly is an epiphenomenon, but that is about all that can be claimed. Eating fruit in my home and then throwing it in the garbage results in garbage. Not throwing that garbage into the incinerator or leaving it on the sidewalk results in garbage buildup. Garbage buildup will attract rats. Rats crowding my kitchen garbage can will scare wifey. Wifey punching me in the face will cause a black eye. Eating fruit does not cause black eyes.

Brief Review – Ship of Fools – Tucker Carlson
—————————————————–
Liberals and the bi-curious should read this. Carlson provides the best current thinking from the right. He does not genuflect to Trump (and even seems dismayed), which perhaps is a conscious effort to win credibility from the reader, so don’t think you’re picking up a propaganda pamphlet. With his television charisma transported to the page, Carlson runs through a dozen or so disparate subjects through his perceptive and historically-informed lens. How left-core issues have become right-core issues (labor) fascinated me. I’m not a keen politics observer but I really enjoyed this as Carlson lauds certain old-line liberal principles (which appeal to me) and have been lost in today’s demagoguery.

Football
———–
The Bills play remarkably well for their record. Their defense made the Patriots look silly and I “sweated” this game substantially. I took the Patriots ML, -13.5 and a tiny bit -21.5. So, I was 3-0 this weekend (Patriots, Panthers, Redskins)! Now if I can only get my poker game moving… I’ll try to post football picks BEFORE the games start. With the return of the old PCs, I am attracted to writing again. I’m still very busy, however! Despite this I am also going to try and pay attention to basketball.

Poker
——–
Someone tried to play a constant all-in/rebuy game against me. That didn’t work. Taking blinds here and there and then getting slammed on AI calls was a quick lesson for villain.

Personal
———–
Thanks to my new friend who sent me works on Real Analysis, Topology and other fields. Math sits at the throne of the mind.

Papers I’ve Read
——————–
A mutation-led search for novel functional domains in MeCP2. Guy et al. Hum Mol Genet 2018.
Nothing too exciting, seems to confirm C-terminus deletions in MeCP2 don’t result in functional deficiency but more quality-control/protein-stability problems. Authors speculate on a drug helping but I think when you’re missing most of the translation product due to transcription truncation there isn’t much hope for small molecule approaches.

Impaired Mitochondrial Dynamics Underlie Axonal Defects in Hereditary Spastic Paraplegias. Denton et al. Hum Mol Genet 2018.
I don’t know much about this family of diseases, so this was a helpful paper to catch up with.

Football / Poker
——————–
Took the Redskins -1 and the Panthers ML. 2/2 this weekend. Staying away from Patriots -14 although that rises to the level of actionable. It’ll be a game-time decision.

Personal
———-
End of the year is approaching! 33.5 months until home. Everything is mostly good here. My bestie is leaving for prison camp.

Glossary
———-
I will be trying to improve this section with sequentially more complete definitions of terms/concepts, hosted on a separate page on my domain. Some of these concepts are very simple but get very complex quickly with more digging.

autophagy – The process of recycling (death) of cellular components.
mitochondria – Cellular organelles that are the main source of ATP. The shape and size of mitochondria are regulated by enzymatic fusion and fission processes. The mitochondria is membrane-enclosed and membrane potential is a measurement of mitochondrial health.
mitophagy – Mitochondrial degradation/autophagy.
negative/purifying selection – The removal of a gene or allele from a species’ gene pool due to disadvantageous properties via natural selection.
Southern Blot – laboratory technique used to detect nucleic acids via hybridization
transcription – The process of transcribing mRNA from a DNA template (gene).
translation – The process of building a protein from a mRNA template.

BGNE has come in a lot, appropriately. Hard to beat Imbruvica and I think you might need an ionic (standard) binder to change things here. Covalent is covalent, amirite?

Big Revlimid, Soliris, Keytruda and Opdivo numbers. Cancer/Rare disease is eating pharmaceuticals. All the basic necessities of statins, metformin, ARBs, antibiotics have been handled. The pharma industry basically exists to manage the 1%-10% of maladies that create 25-50% of healthcare costs. This is a good place to be. No one wants to die of these nasty illnesses and “greed” can’t come into play when you’ve created the first ever treatment for some rare tumor as opposed to improved dry eye symptoms by 30%.

Maybe VKTX is a long in comparison to MDGL. I remember when VKTX couldn’t find a dollar underneath a couch cushion, but that’s life!

Book Review – She Has Her Mother’s Laugh – Carl Zimmer
——————————————————————–

What do we make of “She Has Her Mother’s Laugh”, Carl Zimmer’s latest, and at 600 pages, plumpest work? While ordinarily, I’d say you can skip the theatrics and read Korf’s genetics textbook and keep up with Am J Hum Genet, I still recommend “SHHML” to the layperson and scientist alike.
Zimmer takes disperate fields and has mostly positive results in annealing a reasonable and cohesive narrative that leaves you satisfied. From the history of heredity, which is mostly an exercise in anthropology, and perhaps zoology, Zimmer then tackles the Darwin-Mendel-Lamarck-Galton pre-genetics era with the air of a historian. The problem is that half of this volume is retelling what Gould, Dawkisn and others have already done, and better. There’s far too much “gemmule” and far too little exon.
So why pay attention? First, Zimmer is a tremendous writer. While it took time to finish and synthesize SHHML, there are few moments when the story drugs or is unreadable. Second, Gould is dated: epigenetics, let alone CRISPR, didn’t exist when he was alive. Zimmer impressively weaves bleeding edge advances without temporal distinction. In general, the book moves from the past to the future, but Zimmer prevents SHHML from becoming an encyclopedia by dragging the future backwards and vice versa when appropriate, and by bringing his personal genetics journey into the story to illuminate the science. Unfortunately, this works only to break monotony of what would be a reasonable textbook on the history of genetics–Zimmer feels impersonal and detached. She may have her mother’s laugh, but we never hear the joke.
Another shortcoming is the substantial body of recent advances and basic facets of the subject which are completely left out. We can forgive Zimmer for excising topics like synthetic biology, alternative splicing, vaccines, CART and more, as he’s approaching the limit for a reasonable printing of a somewhat technical subject. This is not Principia Genetica.
Despite this amnesty, Zimmer comes up short when we ventures into a few places, including alternative modes of inheritance. Nodding to the meme, Zimmer nonetheless biopasses prions or any discussion at all of computer science and bioinformatics. Recent papers on algorithms imitating nature and vice versa would have been a nice addition to admittedly already myriad vignettes.
So, occassionally long-winded Zimmer does a great job of explaining sometimes abstract, sometimes concrete and always dense science. We’re left with an awfully preachy and bizarrely placed ending rant on the environment and politics. It would not be a modern mass-market published work without some social justice plea, I suppose. As someone who has made his living off of the subject matter in question, I can’t help but love SHHML. If you’re looking for a modern, up-to-date and reasonably comprehensive history of heredity and genetrics, Zimmer delivers.

Brief Book Review — Molly’s Game – Molly whoever
————————————————————
This vapid scrawl outlining a classic tail of Hollywood failure never leaves the reader feeling sorry for its protagonist. Molly is a preeminent putative overacheiver who doesn’t realize she’s achieved nothing and is a product of parents who haven’t pushed her hard enough despite believing the opposite. Naive Molly doesn’t understand that going from her demeaning cocktail waitress job to “running the poker game” is not a graduation. The wealth of the men leering at you like a delicious pastry does not change the fact you are objectified. Still, she’s the proud poker princess pushing herself to the pinnacle of … party planning? Inevitably poor Molly involves herself (or vice versa) with organized crime and it all comes crashing down. Fuck Molly and the three hours it took to read this sorry chick flick.

Personal
———-
Is it okay to have a crush on Chelsea Clinton?

One life goal is to get served with a lawsuit every day. I probably average around one a month. Gotta step it up.

Wealth is massively increasing again. What to do? Sports teams have gotten stupid expensive for assets that do not produce income (unless I’m not in the know). Paintings seem like better investments–sports is eternal in some ways but shifts quite a bit within 50-100 years.

Biopharma/Investing
—————————
There are many diseases amenable to substrate replacement. I’ve designed some molecules recently.

Papers I’ve Read
——————–
It’s good to be back to my locker(s)-full of journals. Unfortunately I really am in a conflict position on a lot of what I read.There’s very little I’m reading these days that I’m not actively pursuing or have an interest in, so it’s a little unfair to share it here. Just keep that in mind if I seem quiet.

Caliphalaxis. NEJM.
Bad disease, weak paper.

Evidance that Leonardo da Vinci Had Strabismus. JAMA.
They ran a p-value on paintings, LMAO!

Personal
———–
Good news! We’re back in our building after a 3 week relocation. The computers have real keyboards again, perfectly destructible. Sorry I was away–those keyboards were really awful. I’ll try and write more!!! I am amazingly busy as I’ve mentioned. And without reader feedback it’s hard to stay too engaged. If someone wants to step up and actually send me comments so that I can respond, I would definitely do that! If you are on the “CORRLINKS/TRULINCS” system with me, that would work easily. Perhaps my Dad will do it!? It would require not only reading the comments but then posting them to the WordPress site. That’s probably too much for the old man.

Basketball season has started–very exciting. The NFL action this week was fairly predicatable. I stayed away from the Eagles game and thankfully avoided the fate of others who favored the team. The Bills are humorously bad without Allen. The Patriots were the “lock” and delivered. The Vikings were in a similar situation against the woeful Jets. The Browns surprised me, yet again. What an improvement from last year.

Helping inmates here is a challenge. One fellow adds a superfluous -ed to verbs already conjugated with an -ed. When you say that you likeded that album, a part of me dies. Others make small improvements but in general time is spent here entertaining oneself. Whatever TV shows, music, etc. we can be exposed to trumps any self-help. It’s hard to change everyone. Social justice is even harder. I reprimand anyone who utters homophobic slurs but I sense this negative feedback is not always welcome.

Biopharma/Investing
————————-
I like SRPT. Smart management, huge opportunities. Could 10x over the next 5-10 years. Think VRTX or BMRN but bigger and better.

New PFE management. Let’s see what they do with it. Big effort on the alopecia drug. I’d like to see smarter deals. MDVN and ANAC were embarrassing.

ASCO Fall (ESMO) shouldn’t bring much new.

Papers I’ve Read
——————–
Reminder that most of my mail is still in our “old building” which we’ve vacated for repairs.

Sweet Binders: Carbonic Anhydrase IX in Complex with Sucralose. Lomelino et al. ACS Med Chem Lett 2018.
CAIX is of interest to Warburg effect fans (not sure where I stand on that, not very positive at least). I’m sure the authors understand that carbohydrate-based drugs are mostly cell impermeable, but who knows what the carb uptake receptors will pull in…

Clinical Trials I Noticed
—————————-
Dose Escalation and Expansion Study of FLX475 Monotherapy and in Combination with Pembrolizumab. FLX Bio.
This a CCR4 antagonist from the people that brought you the Bristol-Flexus acquisition.

A Study of JNJ-63733657 in Healthy Japanese Participants. Janssen (JNJ).
This is a tau antibody for Alzheimer’s.

A Study to Evaluate the Safety, Tolerability and Pharmacokinetics (PK) of TAK-981 in Adult Participants With Metastatic Solid Tumors or Lymphomas. Takeda.
Mechanism unknown.

EBV-TCR-T (YT-E001) for Patients with EBV-positive Recurrenct or Metastatic NPC. China Immunotech Co., Ltd.
I’m not current on EBV-driven tumors but this looks interesting. China IO in general is fascinating.

BI 655130 Long-Term Treatment in Patients With Moderate-to-Severe Ulcerative Colitis. Boehringer Ingelheim.
This IL-36 antibody had very good results in pustular psoriasis (80% disease activity reduction). No other IL-36 mabs as far as I know…

Researching an Effect of GLP-1 Agonist on Liver STeasosis (REALIST). Trulicity (dulaglutide). Lilly.
I don’t think this trial is very realistic.

Dual mTORc Inhibition in advanced/recurrent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer. Takeda.
This drug, TAK228 aka MLN0128 aka INK128 was acquired from Intellikine. Generic name is sapanisertib. Not sure on how more isoform activity will help.

Glossary
———–
myeloid. The bone marrow lineage which differentiates to granulocytes, monocytes, erythrocytes and platelets. Contrast with lymphoid.
ontogeny. Development of the organism from birth to death. Contrast with phylogeny.
phylogeny. Evolutionary development of a species, throughout time. Contrast with ontogeny.

Biopharma/Investing
————————-
So many distressed generics companies. ACET, LCI, TEVA, AKRX, CXR. There has been a bunch of consolidation: Sandoz/Aurobindo, Teva/Actavis, Amneal/Impax, Aceto/Citron, Lannet/Kremers, Stada/PE, . I think you have to see some more Indian consolidation. Perhaps Sun, Cipla, Lupin or Dr. Reddy’s will flex their muscles.

What do y’all think of the PTCT data?

Boston Pharmaceuticals didn’t get the memo that you can’t have a successful antibiotic company in 2018.

Clinical Trials I Noticed
—————————–
A Clinical Trial to Evaluate the Reversibility of Abacavir/Lamivudine/Dolutegravir CNS-Related Neurotoxicity After Switching to Tenofovir Alafenamide/Emtricitabine/Darunavir/Cobicistat
J&J funded.

Safety and Antitumor Activity Study of Loncastuximab Tesirine and Durvalumab in DLBCL, MCL or FL. ADC Therapeutics.
Safety and Antitumor Activity Study of Loncastuximab Tesirine + Ibrutinib in DLBCL or MCL.
ADC is one of the most exciting private companies. Target here is CD19.

PF-06952229 Treatment in Adult Patients with Advanced Solid Tumors. Pfizer.
Despite the title, this study is enrolling only breast and prostate cancer. My guess is its some androgen/steroid synthesis inhibitor. MOA unknown/unpublished.

A Study of FT2102 in Participants With Advanced Solid Tumors and Gliomas With an IDH1 Mutation. Forma Therapeutics.
Another IDH competitor–this drug, olutasidenib, makes me wonder if AGIO is a short. CELG has a bunch of weird options on Forma’s programs (and company).

Intratumoral AST-008 Combined With Pembrolizumab in Patients with Advanced Solid Tumors. Exicure.
I never understood the whole “stab the tumor with a drug” thing. I suppose there are non-resectable lesions that are still accessible by injection? Anyway, DVAX is doing this, too.

Effect of Shortening the Palatal Extension of the Mouthguard on the Degree of Satisfaction of Water Polo Players. University of Barcelona.
I hope these brave scientists conducting this ground-breaking research are successful.

Psychoeduc Interv. Through Meta-universes on Condom’s Use Self-Efficacy and Sexual Behavior in Students of UAChile.
Speaks for itself, really

Personal
————-
The computers here have new keyboards which are horrible. “The Virtually Indestructible Keyboard” does seem indestructible but it also virtually unusable. I’m an expert typist–I feel bad for the two-finger typers here.

Closing in on 34 months to go. This bid is about how much time I spent in college, not studying.

Football
———-
How good are the Chiefs?!!
My formula says Patriots have an 86% chance of beating the Colts. My other formula says they win by 15 points with R^2=0.5. Line is -10.5 with ML implying 75% win odds.

Biopharma/Investing
————————-
So much to say, so much I should keep to myself!

ALNY had some porphyria biochemical data. I think you have to show attack rate decline in this disease. They will.
ALXN acquisition is interesting. This was one of the hotter private companies.
Novartis job cuts are consistent with every drug company shifting to specialty. This means A LOT fewer jobs across the board (not just manufacturing and S&M).
GERN, TGTX should have been very anticlimactic.

Chemical Approaches to Modulating Complement-Mediated Diseases. Iyet, et al. J Med Chem 2017.
Reasonable review of what should be a more exciting space for pharma than it currently is.

Glanced at a poorly written Italian paper on new, “selective” glucocorticoids, a new IDO inhibitor and a silly CRO-industry white paper masquerding as a journal paper. I think someone should try IDO for CNS given its clearly related mechanism (don’t steal my idea).

Dose-response of Cannabis and Driving. Cannabis vs. placebo. Centre for Addiction and Mental Health.
Hmm. Wouldn’t want to be a participant.

Football
———–
What a week… How do you explain the Bills-Jaguars? There is a sort of unpredictability that strikes some games. Not quite sure how to model it… Personnel changes and personnel history is important to include in the data sets. The QB change there should simply widen a confidence interval. I’m starting to integrate a ELO approach into my other formulas.

How about Brady? Is it over?

Personal
———–
We had to move buildings here while our building is being repaired. The carbon-copy building temporarily housing us is fine. Jail is jail. Unfortunately, almost all of my papers and books had to be left in the old building. I’m reading Zimmer’s “She has her Mother’s Laugh” and a Medical Genetics textbook in the meantime.

Biopharma/Investing
—————————
The cannabis bubble is actionable. I’d short TLRY, WEED, ACB, and the rest, and be patient. If I were at a hedge fund with a big “central book” (Citadel, Bridgewater, Tiger, Soros, Goldman Sachs, Third Point), I’d ask senior management to just write upside volatility or short common stock from here to eternity. Can probably make $500m to $1B.

NASH is probably the last big pharma mass-market/GP indication. Makes me jealous but also annoyed I never took it too seriously.

Clinical Trials
—————–
An Investigational Immunotherapy Study of BMS-986310 Administered Alone and in Combination With Nivolumab in Patients With Advanced Solid Tumors.
I wonder what 986310 is…

Alzheimer’s Disease Treatment with Combination of 40Hz Light and Cognitive Therapy. Alzheimer’s Light LLC.
Who needs drugs when you have light?

Personal
———–
Football season has been interesting.
Yard differential R^2 with point differential is about 0.70 (turnovers, 3rd down/4th down conversion limit R^2 from becoming 1.0). Yet, I see YF-YA as a better indicator of team strength. Turnovers and 3D/4D conversion are more random. I guess I could see which is more predictive of future point differential…
Vegas point spreads seem to have a R^2 of 0.50 to 0.70, which is a little less than what I can get without them.

Biopharma/Investing
—————————
Are there too many antibody-focused companies? There are only so many antibody targets by virtue of their limitations (no intracellular targets). You have JNJ-US, ROG-VX, NOVN-VX, LLY, BMY, SAN-FP, MRK-DE, AMGN, AZN-LN, REGN, GEN-DC, ALXN, SGEN, MOR-DE, MGNX, ANAB, XOMA, etc. Once a target is of interesting, everyone can make one relatively similar product and trial it. There are a lot of potential targets, so does that shift the game to disease biology where are there actually very few intelligent players? Clinical execution is obviously important as well. Maybe we can do an analysis of all new antibody candidates and see how long it took for a fast-follower/competitor to show up…?
Doing this analysis now. My preliminary conclusion after looking at about 200 antibodies is despite the expected chase of exciting targets, there is a lot of stalling and usually more than enough room for multiple entrants. Now, about that biologics capacity…

RIP $VTL, you will be missed.

Wow, BAYN.DE really falling apart.

It will definitely be interesting to see changes in Chinese drug revenue. If you try and look at Sino (1177), it kinda looks like there is a lot of revenue growth (30% y/y) but it’s hard to tell how much is organic. Jiangsu Hengrui is all in Mandarin 🙁 otherwise I’d really like to understand that megacap ($40bn!).

Cannabis-related stocks are or will be epic shorts soon.

Personal
———–
I’ve been working on predictive scoring functions for NFL games. I like the Ravens!